2. Academic Validation
  3. Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors

Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors

  • Bioorg Med Chem Lett. 2014 Sep 15;24(18):4546-4552. doi: 10.1016/j.bmcl.2014.07.071.
Lan Wang 1,  Mark Stanley 1,  Jason W Boggs 2,  Terry D Crawford 1,  Brandon J Bravo 3,  Anthony M Giannetti 3,  Seth F Harris 4,  Steven R Magnuson 1,  Jim Nonomiya 3,  Stephen Schmidt 3,  Ping Wu 4,  Weilan Ye 5,  Stephen E Gould 5,  Lesley J Murray 2,  Chudi O Ndubaku 6,  Huifen Chen 7
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 2 Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3 Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 4 Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 5 Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 6 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 7 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
PMID: 25139565 DOI: 10.1016/j.bmcl.2014.07.071
Abstract

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure.

Keywords

Fragment-based lead discovery; Kinase inhibitors; MAP4K4; P-loop conformation; Pyrrolotriazine.

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